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Prediction: Dopamine Levels Should Be Out of Phase with Prolactin Levels Dopamine secretion into the median eminence and the neural lobe peaks at noon, between the prolactin surges McKee et al., Endocrinology, 148:4649, 2007

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Input from the Suprachiasmatic Nucleus Neurons of the suprachiasmatic nucleus (SCN) that project to the arcuate nucleus and release vasoactive intestinal polypeptide (VIP) are most active early in the morning. They are inhibitory to DA neurons.

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Improved Rhythm Generator Rhythm during one day Rhythm during 10 days CS simulated by partial inhibition of dopamine neurons

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Simulation and Prediction Prediction: The PRL rhythm will return when the OT antagonist leaves the system. That is, OT at the lactotroph is required for the expression of the rhythm, but not for triggering the rhythm. Simulation PRL Time (days) As predicted, the prolactin rhythm comes back once the antagonist clears the system (day 2 – no rhythm; day 3 – rhythm present) (McKee et al., Endocrinology, 148:4649, 2007)

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Conclusions: Part 1 2. The prolactin rhythm can be induced by mating, or in OVX animals, by cervical stimulation, central or peripheral prolactin injection, or peripheral oxytocin injection. 1. The prolactin rhythm is likely due to interactions between dopamine neurons and lactotrophs. 3. Oxytocin at the lactotroph is necessary for the expression of the CS-induced rhythm, but is not part of the triggering mechanism.

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The Amount of Dopamine Arriving in the Anterior Lobe Decreases Coincident with the Rise of Prolactin During the Estrous Cycle

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Does Oxytocin Contribute to the Proestrous Surge? 1. Plasma oxytocin concentration increases in response to estradiol administration (Yamaguchi et al., Endocrinol. Jpn., 26:197, 1979) 2. The concentration of oxytocin in pituitary portal blood peaks on the afternoon of proestrus (Sarkar and Gibbs, Neuroendocrinology, 48:214, 1988) So a role for oxytocin seems plausible

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Does the Oxytocin Sensitivity of Lactotrophs Vary During the Cycle? Our experiments: Remove anterior pituitaries from cycling rats on the morning of diestrus-1 or afternoon of proestrus Disperse cells. Use mixed population for prolactin secretion measurements, enrich for lactotrophs for calcium measurements Apply oxytocin to the pituitary cells

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Conclusions: Part 2 1. Sensitivity of lactotrophs to oxytocin is increased during the afternoon of proestrus. This corresponds to the time of the peak in plasma oxytocin levels, and the prolactin surge. 2. Both the size of the individual calcium responses and the number of cells responding to oxytocin are upregulated on the afternoon of proestrus. Open Question: What is the mechanism of the upregulation of the oxytocin response?

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A review of this talk is freely available online in the July Special Issue: